The protease-activated receptor2 (PAR2)-prostaglandin E2-prostanoid EP receptor axis: A potential bronchoprotective unit in the respiratory tract?

Identification and Characterization of Novel Small-Molecule Protease-Activated Receptor 2 Agonists

“…The possible therapeutic utility of PAR2 agonists is controversial, although therapeutic roles for PAR2 agonists have been proposed (De Campo and Henry, 2006;Henry, 2006). PAR2 activation has been shown to cause airway smooth muscle relaxation (Cicala et al, 2001), primarily in an epithelium-derived, PGE2-dependent manner (Cocks et al, 1999;Kawabata et al, 2004;De Campo and Henry, 2005), and by CGRP and PGE2 (Morello et al, 2005); however, other studies have demonstrated that PAR2 agonists may also cause bronchoconstriction (Schmidlin et al, 2002) through a neural mechanism (Su et al, 2005).…”

“…Convincing evidence has been reported showing that PAR2 receptors mediate many of their actions through a neurogenic mechanism (Ricciardolo et al, 2000;Steinhoff et al, 2000;Fiorucci et al, 2001;Vergnolle et al, 2001;Nguyen et al, 2003;Amadesi et al, 2004;Kawabata et al, 2005;Su et al, 2005;Cenac et al, 2007). Given these physiological roles for PAR2 receptors, PAR2 agonists would be expected to exacerbate most nociceptive and inflammatory processes; however, PAR2 also exerts a protective effect in many settings (Cocks et al, 1999;Cicala et al, 2001;Fiorucci et al, 2001;Kawabata et al, 2004bKawabata et al, , 2006De Campo and Henry, 2005;Morello et al, 2005;D'Agostino et al, 2007), especially in models of asthma and pulmonary inflammation; thus, there may be therapeutic roles for PAR2 agonists (De Campo and Henry, 2006;Henry, 2006). The therapeutic potential for PAR2 antagonists, which relieve symptoms in models of rheumatoid arthritis, appears clearer (Kelso et al, 2006;Cenac et al, 2007).…”

“…PAR2 receptors are widely distributed, with expression throughout the central nervous system, gastrointestinal system, pulmonary system, liver, kidney, exocrine glands (pancreas, salivary glands, tear ducts), heart, vascular tissue, reproductive organs, skin and inflammatory cells including eosinophils, mast cells, macrophages, and neutrophils (D'Andrea et al, 1998; for review, also see Henry, 2006;Ramachandran and Hollenberg, 2008). PAR2 receptors are found on primary spinal afferent neurons coexpressed with substance P, calcitonin gene-related peptide (CGRP), and transient receptor potential vanilloid receptor (TRPV) 1 Amadesi et al, 2004;Dai et al, 2004).…”

Prostaglandin E₂ Inhibits Proteinase-Activated Receptor 2-Signal Transduction through Regulation of Receptor Internalization

“…In this experiment, PAR2-AP was treated for only 5 min, so it was unlikely that PAR2-AP upregulated sufficient expression of COX-2 (inducible COX) protein. However, it has been reported that the stimulation of PAR2 induces activation of COX and release of PGE 2 from airway smooth muscle cells and epithelial cells [8]. Therefore, it is possible that PAR2 activation produces PGE 2 and negatively regulates PAR2 functions.…”

“…On the other hand, PAR1 activation also increases PGE 2 production, which plays an important role as an anti-inflammatory mediator partly by downregulating PAR1 expression [20,27,29]. PGE 2 is also produced by the activation of PAR2 and plays an anti-inflammatory role in lung disease [8]. In contrast to PAR1, however, the effects of PGE 2 on PAR2 are still unclear.…”